IMMUNOPATHOGENESIS OF BULLOUS PEMPHIGOID

大疱性类天疱疮（BP）和妊娠疱疹（HG）是威胁生命的起泡性疾病，其特征在于产生针对半桥粒蛋白BP180和BP230的自身抗体，以及表皮下小泡的形成。 该项目的总体目标是促进我们对这些疾病中免疫病理机制的理解。目前的建议的主要重点是测试的假设，真皮表皮交界处的破坏是由渗透性炎症细胞释放的蛋白水解酶。 具体目标1和2是进一步剖析中性粒细胞的募集和激活机制（即细胞粘附分子和细胞表面受体的作用），并研究嗜酸性粒细胞在表皮下水疱中的可能作用。将在缺乏促炎细胞因子、中性粒细胞迁移相关整合素或活化相关Fc受体的小鼠中进行病原性抗BP180 IgG的被动转移实验。 将通过耗竭和重建实验研究嗜酸性粒细胞的作用。 具体目标3被设计为确定蛋白水解酶和反应性氧化剂在实验BP和HG中的作用，并测试BP180的降解产物是趋化性的假设。 这些蛋白酶缺陷的小鼠将注射致病性IgG。 BP180片段的趋化活性将通过体外和体内趋化性测定来测试。 具体目标4是使用被动转移实验和药理学方法研究抗炎药物在表皮下水疱中的作用和机制。 具体目标5是开发一种新的系统来直接测试来自BP和HG患者血清的自身抗体的致病活性。将这些自身抗体注射到在基底角质形成细胞中表达人BP180的新生转基因小鼠中。 针对人BP180上的特异性抗原位点的亲和纯化的自身抗体也将用于该体内系统中以定位致病性表位。这些研究的结果将对BP和HG以及其他相关疾病患者的护理具有深远的临床意义。

Bullous Pemphigoid (BP) and herpes gestationis (HG) are life-threatening blistering diseases that are characterized by the production of autoantibodies directed against the hemidesmosomal proteins, BPl80 and BP230, and by itie formation of subepidermal vesicles. The overall goal of this project is to advance our understanding of the immunopathological mechanisms operating in these diseases. The major focus of the present proposal is to test the hypothesis that the destruction of the dermal-epidermal junction is caused by proleolytic enzymes released from infiltrating inflammatory cells. Specific aims 1 and 2 are to further dissect the mechanism of recruitment and activation of neutrophils (i.e. the role of cell adhesion molecules and cell surface receptors) and investigate the possible role of eosinophils in subepidermal blistering. Passive transfer experiments with pathogenic anti-BP180 IgG will be performed on mice deficient in proinflammatory cytokines, neutrophil migration-related integrins or activation-related Fc receptors. The role of eosinophils will be investigated by depletion and reconstitution experiments. Specific aim 3 is designed to determine the role of proteolytic enzymes and the reactive oxidants in experimental BP and HG and test the hypothesis that degradation products of BPl80 are chemotactic. Mice deficient in these proteinases will be injected with pathogenic IgG. The chemotactic activity of the BPl80 fragments will be tested by in vitro and in vivo chemotaxis assays. Specific aim 4 is to study effects and mechanisms of action of anti-inflammatory drugs in subepidermal blistering using passive transfer experiments and pharmacologic approaches. Specific aim 5 is to develop a novel system to directly test the pathogenic activity of autoantibodies from BP and HG patients' sera. These autoantibodies will be injected into neonatal transgenic mice expressing human BPl80 in the basal keratinocytes. Affinity-purified autoantibodies against specific antigenic sites on human BPl80 will also be used in this in viva system to map the pathogenic epitopes). The results from these studies will have profound clinical implications in the care of patients with BP and HG and other related diseases.